Substituted indolepyridinium as anti-infective compounds

Abstract

The present invention concerns the compounds of formula (I) their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, wherein n is 1, 2 or 3; R 1 is H, CN, halo, aminoC(═O), C(═O)OH, C 1-4 alkyloxyC(═O), C 1-4 alkylC(═O), mono- or di(C 1-4 alkyl)aminoC(═O), arylaminoC(═O), N-(aryl)-N—(C 1-4 alkyl)aminoC(═O), methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, Het 1 or Het 2 ; R 2 is H, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl and C 3-7 cycloalkyl may be optionally substituted; R 3 is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxyC(═O), aminoC(═O), C 1-4 alkyloxyC(═O), mono- or di(C 1-4 alkyl)aminoC(═O), C 1-4 alkylC(═O), methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 ; for use as a medicine. The invention further relates to a novel subgroup of the compounds of formula (I), and to compositions comprising compounds of formula (I).

1 - 27 . (canceled) 
   
   
       28 . A method of treating or combating infection or disease associated with infection with HIV virus comprising administering to a human subject in need of such treatment an effective amount of a. compound of formula (I) 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or stereoisomeric form, 
       wherein n is 1, 2 or 3; 
       R 1  is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, arylaminocarbonyl, N-(aryl)-N—(C 1-4 alkyl)aminocarbonyl, methanimidamidyl, N-hydroxy-methanimidamidyl, or mono- or di(C 1-4 alkyl)methanimidamidyl, or Het 1 ; 
       R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl and C 3-7 cycloalkyl, each individually and independently, may be optionally substituted with a substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxycarbonyl, C 1-4 alkylcarbonyl, N(R 4a ,R 4b )carbonyl, C 1-4 alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl; 
       R 3  is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonyl, methanimidamidyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 ; 
       R 4a  is hydrogen, C 1-4 alkyl or C 1-4 alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C 1-4 alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxo-thiomorpholinyl; 
       R 4b  is hydrogen, C 1-4 alkyl or C 1-4 alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C 1-4 alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxo-thiomorpholinyl; 
       aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano, nitro, hydroxyC 1-6 alkyl, cyanoC 1-6 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl; 
       Het 1  is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C 1-4 alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, halo, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonyl, oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C 1-4 alkyl;
 provided that the compound of formula (I) is different from 
 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, and 
 2,5-dihydro-5-methyl-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile. 
 
     
   
   
       29 . The method according to  claim 28  wherein n is 1, R 3  is nitro, R 1  is cyano, C 1-4 alkyloxycarbonyl or C 1-4 alkylaminocarbonyl; and R 2  is hydrogen or C 1-6 alkyl. 
   
   
       33 . The method according to  claim 28  wherein
 n is 1 or 2;   R 3  is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 .   
   
   
       34 . The method according to  claim 28  wherein
 R 1  is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, arylaminocarbonyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)-methanimidamidyl, or Het 1 ; and   aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, cyano, nitro; and   Het 1  is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C 1-4 alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, halo, cyano, trifluoromethyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, oxo, thio; and wherein the foregoing isoxazolyl may optionally be substituted with C 1-4 alkyl.   
   
   
       35 . The method according to  claim 28  wherein
 R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl or C 1-10 alkyl substituted with substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl or 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl; and   R 4a  is C 1-4 alkyl; and   R 4b  is C 1-4 alkyl or C 1-4 alkyl substituted morpholinyl.   
   
   
       36 . The method according to  claim 28  wherein
 R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl or C 1-10 alkyl substituted with substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl or 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl; and   aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, cyano, and nitro.   
   
   
       37 . The method according to  claim 28  wherein
 R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl or C 1-10 alkyl substituted with substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl or 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl; and   aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, cyano, and nitro; and   R 4a  is C 1-4 alkyl; and   R 4b  is C 1-4 alkyl or C 1-4 alkyl substituted morpholinyl.   
   
   
       38 . The method according to  claim 28  wherein
 R 3  is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 ; and   Het 1  is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C 1-4 alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 3-7 cycloalkyl, halo, cyano, trifluoromethyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, oxo, thio; and wherein the foregoing isoxazolyl may optionally be substituted with C 1-4 alkyl.   
   
   
       39 . The method according to  claim 28  wherein
 n is 1; and   R 1  is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, arylaminocarbonyl, N-hydroxy-methanimidamidyl, mono- or di(C 1-4 alkyl)-methanimidamidyl or Het 1 ; and   R 2  is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-7 cycloalkyl or C 1-10 alkyl substituted with substituent selected from the group consisting of cyano, NR 4a R 4b , pyrrolidinyl, piperidinyl, 4-(C 1-4 alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R 4a R 4b )carbonyl, C 1-4 alkyloxycarbonyl or 4-(C 1-4 alkyl)-piperazin-1-ylcarbonyl; and   R 3  is nitro, cyano, amino, halo, hydroxy, C 1-4 alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, mono- or di(C 1-4 alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het 1 .   
   
   
       40 . The method according to  claim 28  wherein the compound has the following formula 
     
       
         
         
             
             
         
       
     
   
   
       41 . The method according to  claim 40  wherein R 3  is nitro. 
   
   
       42 . The method according to  claim 40  wherein R 1  is cyano. 
   
   
       43 . The method according to  claim 40  wherein R 1  is C 1-4 alkyloxycarbonyl or C 1-4 alkylaminocarbonyl. 
   
   
       44 . The method according to  claim 40  wherein R 2  is C 2-6 alkyl. 
   
   
       45 . The method according to  claim 28  wherein
 n is 1,   R 1  is cyano, halo or oxadiazolyl optionally substituted with a substituent selected from the group consisting of C 1-4 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, hydroxy, C 1-4 alkoxy, amino, cyano, trifluoromethyl, hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, aminoC 1-4 alkyl, mono- or di(C 1-4 alkyl)aminoC 1-4 alkyl, arylC 1-4 alkyl, aminoC 2-6 alkenyl, mono- or di(C 1-4 alkyl)aminoC 2-6 alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, mono- or di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkylcarbonyl, oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C 1-4 alkyl;   R 2  is C 1-6 alkyl, hydrogen, or C 2-6 alkenyl; and   R 3  is nitro, C 1-6 alkyl optionally substituted with piperidinyl, pyrrolidinyl, N(R 4a R 4b ), morpholinyl, pyridyl, cyano, or 4-(C 1-4 alkyl)-piperazin-1-yl.   
   
   
       46 . The method according to  claim 28  wherein the compound is
 5-Isobutyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-Allyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-Butyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-Ethyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-(2-Morpholin-4-yl-ethyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   5-Methyl-1-(4-nitro-phenyl)-1,5-dihydro-pyrido[3,2-b]indol-2-one;   5-But-3-enyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-(2-pyrrolidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-(2-piperidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-(3-Dimethylamino-propyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   3-Bromo-5-methyl-1-(4-nitro-phenyl)-1,5-dihydro-pyrido[3,2-b]indol-2-one   5-Methyl-1-(3-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-(3-piperidin-1-yl-propyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   5-(4-Morpholin-4-yl-butyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-(4-pyrrolidin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   5-[3-(4-Methyl-piperazin-1-yl)-propyl]-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-Cyanomethyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-(3-Morpholin-4-yl-propyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-(4-piperidin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   5-(4-Dimethylamino-butyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;   1-(4-Nitro-phenyl)-2-oxo-5-pyridin-4-ylmethyl-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;   3-(5-tert-Butyl-[1,2,4]oxadiazol-3-yl)-5-methyl-1-(4-nitro-phenyl)-1,5-dihydro-pyrido[3,2-b]indol-2-one; or   5-Methyl-1-(4-nitro-phenyl)-3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-1,5-dihydro-pyrido[3,2-b]indol-2-one; or a pharmaceutically acceptable salt or stereoisomer thereof.   
   
   
       47 . The method according to  claim 28  in which the reverse transcriptase of the HIV virus is mutant.